Reprogramming Retinal Microglia Polarization by Efferocytosis-Mimicking Nanoparticles for Ameliorating Diabetic Retinopathy

Diabetic retinopathy (DR), as the most common microvascular complication of diabetes, seriously threatens the vision of diabetic patients. As the resident phagocytes of the retina, microglia participate in inflammation, neovascularization, and neurodegeneration of DR. Herein, apoptotic retinal cell membrane-coated, rapamycin-loaded mesoporous Prussian blue NPs as immunomodulators for ameliorating DR by modulating microglial polarization are reported. The apoM@mPB@Ra NPs exhibited favorable stability and biocompatibility and achieved active targeted delivery due to the specific recognition between "eat me" signal expressed on apoptotic membrane and microglia. In an LPS-induced cellular inflammation model, apoM@mPB@Ra NPs effectively promoted microglial polarization toward the anti-inflammatory phenotype (M2) by scavenging intracellular reactive oxygen species (ROS) combined with affecting the mTOR signaling pathway, leading to downregulation of pro-inflammatory cytokines IL-6 and TNF-α. Meanwhile, owing to the multienzyme-like activities of mPB in nanoparticles, apoM@mPB@Ra NPs obviously alleviated cellular hypoxia, thereby decreasing the expression of VEGF. Notably, in a mouse model of DR, intravitreally injected apoM@mPB@Ra NPs significantly improved the severity of the abnormal retinal vascular network and inflammatory microenvironment of retinopathy by down-regulating the expression of HIF-1α, VEGF, and inflammatory-related cytokines. Collectively, these findings demonstrate that apoM@mPB@Ra NPs provide a promising and effective approach for the treatment of DR.